Abstract

BACKGROUND:

Substance abuse during pregnancy results in persistent affective and behavioral deficits in drug-exposed children, and increased rates of substance abuse have been observed in young adults prenatally exposed to drugs of abuse. Animal models of prenatal cocaine exposure have yielded differing results depending on the behavioral method used to assess drug potency.

METHODS:

The effects of cocaine, the dopamine D1 agonists SKF-81297 and SKF-82958, and the D2 agonist quinpirole on intracranial self-stimulation were measured in adult Swiss-Webster mice exposed to cocaine in utero (40 mg/kg/day) and vehicle controls with the curve-shift method of brain stimulation-reward (BSR) threshold determination.

RESULTS:

The reward-potentiating effects of cocaine (0.3-30 mg/kg IP) and SKF-82958 but not SKF-81297 on BSR were increased in adult male but not female mice after prenatal cocaine exposure. Quinpirole exerted biphasic effects on BSR, both elevating (0.1-0.3 mg/kg IP) and lowering (1.0-10 mg/kg IP) reward thresholds. Both effects of quinpirole were also enhanced in adult male mice after prenatal cocaine exposure.

CONCLUSIONS:

Prenatal cocaine exposure results in increased reward-potentiating potency of cocaine on BSR in adult mice in a sexually-dimorphic manner. This augmented rewarding effect of cocaine is also associated with increased sensitivity to both D1- and D2-selective agonists.

Intracranial self-stimulation electrode placements in the medial forebrain bundle of adult Swiss-Webster mice at the level of the lateral hypothalamus. Locations of electrode tips are plotted on templates from the standard mouse stereotaxic atlas [29] by manual inspection of Nissl-stained sections. Note that all electrodes were implanted on the right; tip placements in females are shown on the left for clarity. Gray Circles = SAL mice; Black Circles = COC40 mice. See Materials and Methods for details.

Changes in maximum rate of operant response following acute administration of cocaine or saline vehicle. Values at each time point are plotted as mean percentages of the average of 30 minutes of pre-injection maximum response rates ± S.E.M.; n values are identical to Figure 2. See Results for details.

Changes in ICSS thresholds (θ0) following acute administration of the D1-agonist SKF-81297 or saline vehicle. Values at each time point are plotted as a percentage of the average of 30 minutes of pre-injection reward thresholds ± S.E.M. Note the difference in y–axis scale between this figure and Figure 2. n = 4 SAL males; 7 COC40 males; 8 SAL females; and 8 COC40 females. * = Tukey’s P<0.05 vs. saline. See Results for details.

Changes in maximum rate of operant response following acute administration of quinpirole or saline vehicle. Each dose-response curve represents one 15-minute post-injection epoch. Values at each dose are plotted as a percentage of the average of 30 minutes of pre-injection maximum response rates ± S.E.M.; n values are identical to Figure 9. * = Tukey’s P<0.05 vs. saline. See Results for details.